US10098834B2 - Extended release of neuregulin for treating heart failure - Google Patents

Extended release of neuregulin for treating heart failure Download PDF

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US10098834B2
US10098834B2 US14/892,183 US201414892183A US10098834B2 US 10098834 B2 US10098834 B2 US 10098834B2 US 201414892183 A US201414892183 A US 201414892183A US 10098834 B2 US10098834 B2 US 10098834B2
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neuregulin
day
nrg
mammal
administration
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US20160089329A1 (en
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Mingdong Zhou
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Zensun Shanghai Science and Technology Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1883—Neuregulins, e.g.. p185erbB2 ligands, glial growth factor, heregulin, ARIA, neu differentiation factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the invention relates generally to compositions and methods for preventing, treating or delaying various cardiovascular diseases or disorders especially heart failure by extended release of neuregulin.
  • this invention relates to the administration of neuregulin to a mammal via subcutaneous infusion with a pump.
  • Heart failure affects approximately five million Americans, and more than 550,000 new patients are diagnosed with the condition each year.
  • Current drug therapy for heart failure is primarily directed to angiotensin-converting enzyme (ACE) inhibitors, which are vasodilators that cause blood vessels to expand, lowering blood pressure and reducing the heart's workload. While the percent reduction in mortality has been significant, the actual reduction in mortality with ACE inhibitors has averaged only 3%-4%, and there are several potential side effects. Additional limitations are associated with other options for preventing or treating heart failure. For example, heart transplantation is clearly more expensive and invasive than drug treatment, and it is further limited by the availability of donor hearts. Uses of mechanical devices, such as biventricular pacemakers, are similarly invasive and expensive. Thus, there has been a need for new therapies given the deficiencies in current therapies.
  • ACE angiotensin-converting enzyme
  • NRGs a family of EGF-like growth factors
  • NRGs comprises a family of structurally related growth and differentiation factors that include NRG1, NRG2, NRG3 and NRG4 and isoforms thereof, are involved in an array of biological responses: stimulation of breast cancer cell differentiation and secretion of milk proteins; induction of neural crest cell differentiation to Schwann cells; stimulation of skeletal muscle cell synthesis of acetylcholine receptors; and, promotion of myocardial cell survival and DNA synthesis.
  • neuregulin is essential for heart and neural development.
  • NRGs bind to the EGF receptor family, which comprises EGFR, ErbB2, ErbB3 and ErbB4, each of which plays an important role in multiple cellular functions, including cell growth, differentiation and survival. They are protein tyrosine kinase receptors, consisting of an extracellular ligand-binding domain, transmembrane kinase domain and cytoplasmic tyrosine kinase domain.
  • NRG binds to the extracellular domain of ErbB3 or ErbB4, it induces a conformational change that leads to heterodimer formation between ErbB3, ErbB4 and ErbB2 or homodimer formation between ErbB4 itself, which results in phosphorylation of the receptor's C-terminal domain inside the cell membrane.
  • the phosphorylated intracellular domain then binds additional signal proteins inside the cell, activating the corresponding downstream AKT or ERK signaling pathway, and inducing a series of cell reactions, such as stimulation or depression of cell proliferation, cell differentiation, cell apoptosis, cell migration or cell adhesion.
  • these receptors mainly ErbB2 and ErbB4 are expressed in the heart.
  • NRG-1 neuregulin-1 ⁇
  • ErbB2 The orphan receptor, ErbB2
  • ErbB3 can form heterodimer with ErbB3 and ErbB4 with higher affinity than ErbB3 or ErbB4 homodimers.
  • Research in neural development has indicated that the formation of the sympathetic nervous system requires an intact NRG-1 ⁇ , ErbB2 and ErbB3 signaling system. Targeted disruption of the NRG-1 ⁇ or ErbB2 or ErbB4 led to embryonic lethality due to cardiac development defects.
  • NRG-1 ⁇ has been shown to enhance sarcomere organization in adult cardiomyocytes. Extended release of NRG via intravenous infusion significantly improves or protects against deterioration in myocardial performance in distinct animal models of heart failure as well as in clinical trials. These results make NRG-1 promising as a lead compound for the treatment of heart failure. While the administration of NRG to the patients via intravenous infusion for consecutive days at hospital is to some extent inconvenient and expensive, there is a need to develop an effective and convenient method of using NRG for the prevention, treatment or delaying of cardiovascular diseases, in particular, heart failure.
  • NRG neuregulin
  • This invention further provides compositions and methods for preventing, treating or delaying various cardiovascular diseases or disorders especially heart failure by extended release of NRG through subcutaneous infusion to a mammal, particularly in humans.
  • this invention relates to compositions and methods for preventing, treating or delaying various cardiovascular diseases or disorders, especially heart failure, by extended release of NRG using a portable mini pump for subcutaneous infusion.
  • NRG enhances cardiac muscle cell differentiation and organization of sarcomeric and cytoskeleton structure, as well as cell adhesion. It has been also discovered by applicant that NRG through intravenous infusion significantly improves or protects against deterioration in myocardial performance in distinct animal models of heart failure and in clinical trials. Neuregulin, neuregulin polypeptide, neuregulin derivatives, or compounds which mimic the activities of neuregulins, fall within the scope of the present invention.
  • a method for preventing, treating or delaying various cardiovascular diseases or disorders, especially heart failure comprising providing extended release of neuregulin into a mammal in need thereof.
  • the extended release of neuregulin into a mammal enhances the EF values of the left ventricle of mammal.
  • the extended release of neuregulin into a mammal reduces Left Ventricular End-Diastolic Volume (LVEDV) or Left Ventricular End-Systolic Volume (LVESV).
  • the extended release of neuregulin into a mammal improves six minute walk distance and quality of life.
  • the extended release of neuregulin into a mammal reduces side effects.
  • the extended release of neuregulin into a mammal comprises the use of a mini pump.
  • the extended release of neuregulin into a mammal is administered by subcutaneous infusion.
  • an extended release composition or formulation of neuregulin for preventing, treating or delaying various cardiovascular diseases or disorders, especially heart failure.
  • using the compositions or formulations of neuregulin enhances the EF values of the left ventricle of a mammal.
  • using the compositions or formulations of neuregulin reduces Left Ventricular End-Diastolic Volume (LVEDV) or Left Ventricular End-Systolic Volume (LVESV).
  • using the compositions or formulations of neuregulin improves of six minute walk distance and quality of life.
  • using the compositions or formulations of neuregulin reduces side effects.
  • the extended release composition or formulation of neuregulin is administered by subcutaneous infusion with a pump, for example, a syringe pump.
  • a pump for example, a syringe pump.
  • the syringe pump is a mini pump.
  • the mini pump is an insulin pump.
  • an effective dose and/or an effective dose range of extended release neuregulin is provided for preventing, treating or delaying various cardiovascular diseases or disorders especially heart failure.
  • the neuregulin is administered by subcutaneous infusion.
  • the effective dose of neuregulin is 0.3 ⁇ g/kg.
  • the effective dose of neuregulin is 1.2 ⁇ g/kg.
  • the effective dose of neuregulin is 2.0 ⁇ g/kg.
  • the effective dose of neuregulin is 3.0 ⁇ g/kg.
  • an effective dose range of neuregulin is 0.3-3.0 ⁇ g/kg.
  • an effective dose range of neuregulin is 1.2-2.0 ⁇ g/kg.
  • the present invention provides a kit comprising a neuregulin composition or formulation and a portable mini pump.
  • the kit further comprises an instruction for using the kit for preventing, treating or delaying heart failure in a mammal.
  • the portable mini pump is an insulin pump.
  • FIG. 1 Results of LVEF % at baseline and day 30.
  • FIG. 2 LVEF % absolute change at day 30 compared to baseline.
  • FIG. 3 Results of LVEDV at baseline and day 30.
  • FIG. 4 LVEDV absolute change at day 30 compared to baseline.
  • FIG. 5 Results of LVESV at baseline and day 30.
  • FIG. 6 LVESV absolute change at day 30 compared to baseline.
  • FIG. 7 Results of increased walk distance at day 30 compared to baseline.
  • FIG. 8 Results of post walk dyspnea at day 30 compared to baseline.
  • FIG. 9 Results of post walk fatigue at day 30 compared to baseline.
  • FIG. 10 Change of quality of life score at day 30 compared to baseline.
  • FIG. 11 Percentage of NYHA classification at baseline and day 30.
  • Neuregulin or “NRG” used in the present invention refers to proteins or peptides that can bind and activate ErbB2, ErbB3, ErbB4 or combinations thereof, including but not limited to all neuregulin isoforms, neuregulin EGF-like domain alone, polypeptides comprising neuregulin EGF-like domain, neuregulin mutants or derivatives, and any kind of neuregulin-like gene products that also activate the above receptors as described in detail below.
  • Neuregulin also includes NRG-1, NRG-2, NRG-3 and NRG-4 proteins, peptides, fragments and compounds that mimic the activities of neuregulin.
  • Neuregulin used in the present invention can activate the above ErbB receptors and modulate their biological reactions, e.g., stimulate acetylcholine receptor synthesis in skeletal muscle cell; and/or improve cardiocyte differentiation, survival and DNA synthesis.
  • Neuregulin also includes those variants with conservative amino acid substitutions that do not substantially alter their biological activity. Suitable conservative substitutions of amino acids are known to those of skill in the art and may be made generally without altering the biological activity of the resulting molecule.
  • neuregulin used in the present invention binds to and activates ErbB2/ErbB4 or ErbB2/ErbB3 heterodimers, for example, but not for the purpose of restriction, peptides including the 177-237 residues of NRG-1 ⁇ 2 isoform containing the amino acid sequence: SHLVKCAEKEKTFCVNGGECF MVKDLSNPSRYLCKCPNEFTGDRCQNYVMASFYKAEELYQ (SEQ ID NO:1).
  • the peptides including the 177-237 residues of NRG-1 ⁇ 2 isoform comprise the EGF-like domain, which has been proved to be sufficient to bind to and activate the receptors.
  • EGF-like domain refers to a polypeptide motif encoded by the neuregulin gene that binds to and activates ErbB2, ErbB3, ErbB4, or combinations thereof, and bears a structural similarity to the EGF receptor-binding domain as disclosed in WO 00/64400, Holmes et al., Science , 256:1205-1210 (1992); U.S. Pat. Nos. 5,530,109 and 5,716,930; Hijazi et al., Int. J. Oncol.
  • EGF-like domain binds to and activates ErbB2/ErbB4 or ErbB2/ErbB3 heterodimers.
  • EGF-like domain comprises the amino acid sequence of the receptor binding domain of NRG-1.
  • EGF-like domain comprises the amino acid sequence corresponding to amino acid residues 177-226, 177-237, or 177-240 of NRG-1 (amino acid residues 177-226 SHLVKCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCPNEFTGDRCQNYVM (SEQ ID NO:2); amino acid residues 177-240 SHLVKCAEKEKTFCVNGGECFMVKDLSNPSRYLC KCPNEFTGDRCQNYVMASFY KAEELYQKRV (SEQ ID NO:3)), each of which is considered to be an exemplary neuregulin of the invention.
  • EGF-like domain comprises the amino acid sequence of the receptor binding domain of NRG-2.
  • EGF-like domain comprises the amino acid sequence of the receptor binding domain of NRG-3. In certain embodiments, EGF-like domain comprises the amino acid sequence of the receptor binding domain of NRG-4. In certain embodiments, EGF-like domain comprises the amino acid sequence of Ala Glu Lys Glu Lys Thr Phe Cys Val Asn Gly Gly Glu Cys Phe Met Val Lys Asp Leu Ser Asn Pro (SEQ ID NO:4), as described in U.S. Pat. No. 5,834,229.
  • the neuregulin protein can be formulated for oral, topical, inhalational, buccal (e.g., sublingual), parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), transdermal administration or any other suitable route of administration.
  • buccal e.g., sublingual
  • parenteral e.g., subcutaneous, intramuscular, intradermal, or intravenous
  • transdermal administration e.g., transdermal administration or any other suitable route of administration.
  • the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular neuregulin protein, which is being used.
  • the neuregulin protein can be administered alone. Alternatively and preferably, the neuregulin protein is co-administered with a pharmaceutically acceptable carrier or excipient.
  • Any suitable pharmaceutically acceptable carrier or excipient can be used in the present method (See e.g., Remington: The Science and Practice of Pharmacy , Alfonso R. Gennaro, ed., Mack Publishing Company, April 1997; and Remington's Pharmaceutical Sciences, 18th ed., Gennaro, ed., Mack Publishing Co. (1990)).
  • a “pump” is a drug delivery device that employs subcutaneous infusions of therapeutic fluids, drugs, proteins, and/or other compounds and has the property of continuous precise dosing of the medication in their supply.
  • a pump can employ a subcutaneous catheter for continuous subcutaneous infusion.
  • the catheter can be external or the catheter port can be embedded into the pump mechanism.
  • a mini pump is a device which can export fluids accurately and it is portable and handy.
  • an insulin pump is a medical device used for the administration of insulin or other agents in the treatment of diabetes mellitus or other diseases, also known as continuous subcutaneous insulin infusion therapy.
  • An insulin pump can be configured to be attached to a disposable thin plastic tube or a catheter through which insulin or other drug substance passes into the tissue.
  • a pump can be configured in external devices, which connect to a patient, and can be configured in implantable devices, which are implanted inside of the body of a patient.
  • External pumps can include devices designed for use in a stationary location, such as a hospital, a clinic, or the like, and further can include devices configured for ambulatory or portable use, such as pumps designed to be carried by a patient, or the like.
  • External pumps contain reservoirs of fluidic media, such as, but not limited to, fluidic media containing neuregulin protein.
  • External pumps can be connected in fluid flow communication to a patient, for example, through suitable hollow tubing.
  • the hollow tubing can be connected to a hollow needle that is designed to pierce the skin of the patient and to deliver fluidic media there through.
  • the hollow tubing can be connected directly to the patient as through a cannula, or the like.
  • An external pump can be worn or otherwise attached on or underneath clothing of the patient.
  • suitable pumps include, but are not limited to, the MiniMed Paradigm 522 Insulin Pump, MiniMed Paradigm 722 Insulin Pump, MiniMed Paradigm 515 Insulin Pump, MiniMed Paradigm 715 Insulin Pump, MiniMed Paradigm 512R Insulin Pump, MiniMed Paradigm 712R Insulin Pump, MiniMed 508 Insulin Pump, MiniMed 508R Insulin Pump (Medtronic; Northridge, Calif.), and any similar devices known by those skilled in the art.
  • compositions and methods for their administration that may be employed for use in this invention include, but are not limited to, those described in U.S. Pat. Nos. 5,736,154; 6,197,801; 5,741,511; 5,886,039; 5,941,868; 6,258,374; and 5,686,102.
  • the neuregulin protein may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier or excipient, such as beta-cyclodextrin and/or 2-hydroxy-propyl-beta-cyclodextrin, according to conventional pharmaceutical compounding techniques.
  • a pharmaceutical carrier or excipient such as beta-cyclodextrin and/or 2-hydroxy-propyl-beta-cyclodextrin, according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide form of preparation desired for administration, topical or parenteral.
  • similar pharmaceutical media may be employed, including but not limited to water, glycols, oils, buffers, sugar, preservatives, liposomes, stabilizing agents, and the like known to those of skill in the art.
  • parenteral compositions include, but are not limited to dextrose 5% w/v, normal saline or other solutions.
  • Exemplary buffers include, but are not limited to, acetate, citrate and phosphate.
  • Exemplary stabilizing agents include, but are not limited to, proteins such as albumin, for example, human serum albumin, gelatin, and the like.
  • Exemplary sugars include, but are not limited to, glucose (dextrose), sucrose, fructose, mannitol, sorbitol, and the like.
  • Exemplary salts include, but are not limited to, potassium bicarbonate, sodium bicarbonate, potassium chloride, sodium chloride and the like.
  • the total dose of the neuregulin protein, alone or in combination with other agents to be administered, may be administered in a vial of intravenous fluid, ranging from about 1 ml to 2000 ml.
  • kits of the invention further comprises a needle or syringe, preferably packaged in sterile form, for injecting the composition, and/or a packaged alcohol pad. Instructions are optionally included for administration of the composition by a physician or by the patient.
  • protein is synonymous with “polypeptide” or “peptide” unless the context clearly dictates otherwise.
  • activity unit or “EU” or “U” means the quantity of standard product that can induce 50% maximal reaction.
  • the EC50 must be measured. For example, if the EC50 for a batch of product was 0.1 ⁇ g, then that would be one unit. Further, if 1 ⁇ g of that product is being used, then 10 EU (1/0.1) is being used.
  • the EC50 can be determined by any method known in the art suitable for making such a determination, including the method employed by the inventors as disclosed herein. This determination of the activity unit is important for quality control of genetically engineered products and clinically used drugs, and permits product from different pharmaceuticals and/or different batch numbers to be quantified with uniform criteria.
  • the following is an exemplary, rapid, sensitive, high flux and quantitative method for determination of biological activity of NRG-1 through combining NRG with cell surface ErbB3/ErbB4 molecule and indirect mediation of ErbB2 phosphorylation (See e.g., Michael D. Sadick et al., 1996 , Analytical Biochemistry, 235:207-214 and WO03/099300).
  • the assay termed a kinase receptor activation enzyme-linked immunosorbant assay (KIRA-ELISA)
  • KIRA-ELISA kinase receptor activation enzyme-linked immunosorbant assay
  • the assay was developed for analysis of NRG-induced ErbB2 activation and utilizes the stimulation of intact receptor on the adherent breast carcinoma cell line, MCF-7.
  • Membrane proteins are solubilized via Triton X-100 lysis and the receptor is captured in ELISA wells coated with ErbB2-specific antibodies with no cross-reaction to ErbB3 or ErbB4.
  • the degree of receptor phosphorylation is then quantified by antiphosphotyrosine ELISA.
  • a reproducible standard curve is generated with an EC50 of approximately 360 pM for heregulin beta 1 (177-244) (amino acid residues 177-244 SHLVKCAEKEKTFCVNGGECFMVKDLSNPSRYLC KCPNEFTGDRCQNYVMASFY KAEELYQKRVLTIT (SEQ ID NO:5)).
  • HRG beta 1 177-244
  • the assay described in this report is able to specifically quantify tyrosine phosphorylation of ErbB2 that results from the interaction of HRG with ErbB3 and/or ErbB4.
  • Quantity of standard product that can induce 50% maximal reaction is defined as an activity unit (1 EU). Accordingly, product from different pharmaceuticals and of different batch numbers can be quantified with uniform criteria.
  • an “effective dose” of an active agent for preventing, treating or delaying a particular disease is a dose that is sufficient to ameliorate, or in some manner reduce the symptoms associated with the disease.
  • the dose may cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease.
  • an effective dose of neuregulin can be at least 0.2 ⁇ g/kg/day, 0.3 ⁇ g/kg/day, 0.4 ⁇ g/kg/day, 0.5 ⁇ g/kg/day, 0.6 ⁇ g/kg/day, 0.7 ⁇ g/kg/day, 0.8 ⁇ g/kg/day, 0.9 ⁇ g/kgday, 1.0 ⁇ g/kg/day, 1.1 ⁇ g/kg/day, 1.2 ⁇ g/kg/day, 1.3 ⁇ g/kg/day, 1.4 ⁇ g/kg/day, 1.5 ⁇ g/kg/day, 1.6 ⁇ g/kg/day, 1.7 ⁇ m/kg/day, 1.8 ⁇ g/kg/day, 1.9 ⁇ g/kg/day, 2.0 ⁇ g/kg/day, 2.1 ⁇ g/kg/day, 2.2 ⁇ g/kg/day, 2.3 ⁇ g/kg/day, 2.4 ⁇ g/kg/day, 2.5 ⁇ g/kg/day, 2.6
  • an effective dose of neuregulin is 1.2 ⁇ g/kg/day. In another embodiment, an effective dose of neuregulin is 2.0 ⁇ g/kg/day. In one embodiment, an effective dose of neuregulin is 3.0 ⁇ g/kg. In one embodiment, an effective dose range of neuregulin is 0.3-3.0 ⁇ g/kg/day. In one embodiment, an effective dose range of neuregulin is 1.2-2.0 ⁇ g/kg/day.
  • active agent means any substance intended for the diagnosis, cure, mitigation, treatment, or prevention of disease in humans and other animals, or to otherwise enhance physical and mental well-being.
  • amelioration of the symptoms of a particular disorder by administration of a particular active agent refers to any lessening, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the agent.
  • treat refers to any manner in which the symptoms of a condition, disorder or disease are ameliorated or otherwise beneficially altered.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof, and/or the effect may be therapeutic in terms of a partial or complete reduction of a sign or symptom associated with a disease, cure for a disease and/or reducing an adverse effect attributable to the disease.
  • Treatment also encompasses any pharmaceutical use of the compositions herein.
  • heart failure means an abnormality of cardiac function where the heart does not pump blood at the rate needed for the requirements of metabolizing tissues.
  • Heart failure includes a wide range of disease states such as congestive heart failure, myocardial infarction, tachyarrhythmia, familial hypertrophic cardiomyopathy, ischemic heart disease, idiopathic dilated cardiomyopathy, myocarditis and the like.
  • the heart failure can be caused by any number of factors, including, without limitation, ischemic, congenital, rheumatic, viral, toxic or idiopathic forms.
  • Chronic cardiac hypertrophy is a significantly diseased state which is a precursor to congestive heart failure and cardiac arrest.
  • ejection fraction means the portion of blood that is pumped out of a filled ventricle as the result of a heartbeat. It may be defined by the following formula: (LV diastolic volume ⁇ LV systolic volume)/LV diastolic volume.
  • the present invention provide methods and compositions for extended release of neuregulin for preventing, treating or delaying various cardiovascular diseases or disorders, such as heart failure.
  • Extended release of neuregulin allows for simplification of administration scheme, improves clinical efficacy and attenuates adverse events, e.g., related to high blood level of neuregulin. It is contemplated that extended release of neuregulin over a certain period of time could induce or maintain expression of certain genes for cardiomyocyte growth and/or differentiation, remodeling of muscle cell sarcomeric and cytoskeleton structures, or cell-cell adhesions.
  • Extended release of neuregulin provides a continuous therapeutic level of neuregulin over a period of time.
  • neuregulin is released over a period of 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours or longer.
  • neuregulin is released over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or longer.
  • neuregulin is released over a period of 1 week, 2 weeks, 3 weeks, 4 weeks or longer. The administration can optionally occur for consecutive hours or on consecutive days or weeks, if desired.
  • neuregulin is released over a period of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In another embodiment, neuregulin is released over a period of 1 year, 2 years, 3 years, 4 years, 5 years, or longer. In some embodiments, neuregulin is released over a period of between 1 hour and 2 weeks, between 2 hours and 2 weeks, between 4 hours to 24 hours, between 4 days and 10 days. The amount of time over which neuregulin is released may depend on various factors such as the extended release technology or technologies used.
  • Neuregulin can also be administered in a dosing schedule or “therapeutic cycle”. Daily dosage of neuregulin in the therapeutic cycle is described in detail below.
  • the therapeutic cycle can last 2 days, 5 days, 7 days, 10 days, two weeks, 1 month, 3 month, 6 month, 1 year or longer.
  • the recommended daily dose range of neuregulin per kilogram of body weight of the patients in the methods of the invention for the conditions described herein lie within the range of from about 0.001 ⁇ g to about 1000 mg per day.
  • a total daily dose range per kilogram of body weight of the patients should be between 0.001 ⁇ g per day and 15 mg per day, 0.005 ⁇ g per day and 10 mg per day, 0.01 ⁇ g per day and 5 mg per day, 0.1 ⁇ g per day and 1 mg per day, 0.5 ⁇ g per day and 100 ⁇ g per day, 1 ⁇ g per day and 10 ⁇ g per day, 1.2 ⁇ g per day and 2.4 ⁇ g per day, 1.2 ⁇ g per day and 2.2 ⁇ g per day, or 1.2 ⁇ g per day and 2.0 ⁇ g per day.
  • the therapy can be initiated at a lower dose, perhaps about 0.1 ⁇ g to about 0.3 ⁇ g, and increased if necessary up to about 1 ⁇ g to 1000 ⁇ g per day as either a single dose or divided doses, depending on the patient's global response. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art.
  • neuregulin is administered daily for each day of the therapeutic cycle. In certain embodiments, neuregulin is administered consecutively for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 2 weeks, 1 month, 3 months, 6 months, 1 year or longer. In certain embodiments, neuregulin is administered to the patients for an induction regimen. In some optimized embodiments, the induction regimen includes an administration of neuregulin for at least 3, 5, 7, 10 or 15 consecutive days. In some optimized embodiments, the induction regimen includes administration of neuregulin at least 2, 4, 6, 8, 10, 12, 16, 20, 24 consecutive hours every day.
  • neuregulin is administered to the patients for a maintenance regimen for at least 3 months, 6 months, 12 months, 1 year, 5 years or even longer after the induction regimen. It is understood that other time periods disclosed herein can be used for an induction or maintenance regimen.
  • the invention provides a method for preventing, treating or delaying a cardiovascular disease or disorder in a mammal, the method comprising subcutaneous extended release of neuregulin into a mammal in an amount of 0.3 ⁇ g/kg/day to 3.0 ⁇ g/kg/day, wherein the subcutaneous extended release of neuregulin into a mammal is accomplished through the use of a pump.
  • the extended release of neuregulin can be provided by administering neuregulin in an extended release formulation, such as a suitable formulation for administering by use of a pump.
  • the invention provides a method for preventing, treating or delaying a cardiovascular disease or disorder in a mammal, the method comprising administering subcutaneously an extended release of neuregulin into a mammal in an amount of 0.3 ⁇ g/kg/day to 3.0 ⁇ g/kg/day, wherein the subcutaneous extended release of neuregulin into a mammal is accomplished through the use of a pump.
  • the disease or disorder being treated with neuregulin is heart failure, for example, in a mammal such as a human.
  • the subcutaneous extended release of neuregulin into a mammal is accomplished through the use of a syringe pump.
  • the syringe pump can be, for example, a mini pump such an insulin pump.
  • the neuregulin can in an amount of 1.2 ⁇ g/kg/day to 2.0 ⁇ g/kg/day, or other amounts disclosed herein.
  • the neuregulin is in an amount of 1.2 ⁇ g/kg/day.
  • the neuregulin is in an amount of 2.0 ⁇ g/kg/day.
  • the neuregulin is in an amount of 6 EU/kg/day to 60 EU/kg/day.
  • the neuregulin is in an amount of 24 EU/kg/day to 40 EU/kg/day.
  • the neuregulin is in an amount of 24 EU/kg/day.
  • the neuregulin is in an amount of 40 EU/kg/day.
  • the neuregulin can be administered to the mammal for an induction regimen.
  • the induction regimen includes an administration of neuregulin for at least 3, 5, 7, 10 or 15 consecutive days. It is understood that other number of days of administration can be used, if desired, as disclosed herein.
  • the neuregulin can be administered for at least 2, 4, 6, 8, 10, 12, 16, 20, 24 consecutive hours every day. It is understood that other number of hours of administration can be used, if desired, as disclosed herein.
  • the neuregulin is administered to the patients for a maintenance regimen after the induction regimen.
  • the maintenance regimen can include an administration of neuregulin for at least 3 months, 6 months, 12 months, 5 years or even longer after the induction regimen.
  • the maintenance regimen includes a repeat of the induction regimen every 3 months, 6 months or 12 months.
  • the extended release of neuregulin into a mammal enhances the ejection fraction (EF) value of the mammal.
  • the ejection fraction (EF) represents the volumetric fraction of blood pumped out of the left and right ventricle with each heartbeat or cardiac cycle. Methods of measuring the ejection fraction are well known to those skilled in the art.
  • the extended release of neuregulin into a mammal reduces the Left Ventricular End-Diastolic Volume (LVEDV) of the mammal.
  • LVEDV Left Ventricular End-Diastolic Volume
  • the end-diastolic volume (EDV) is the volume of blood in the right and/or left ventricle at end load or filling in (diastole).
  • the extended release of neuregulin into a mammal reduces the Left Ventricular End-Systolic Volume (LVESV) of the mammal.
  • LVESV Left Ventricular End-Systolic Volume
  • ESV end-systolic volume
  • the extended release of neuregulin into a mammal improves 6 Minute Walk Distance (6 MWD) of the mammal.
  • the extended release of neuregulin into a mammal improves quality of life of the mammal. The effectiveness of neuregulin at improving measurements of heart disease and/or improved patient outcomes are described herein in the Examples.
  • the invention additional provides a kit for preventing, treating or delaying a cardiovascular disease or disorder in a mammal, the kit comprising a neuregulin composition or formulation and a pump.
  • the kit can be used, for example, to treat a patient having a disease or disorder that is heart failure.
  • the patient can be a mammal such as a human.
  • the pump can be a syringe pump.
  • the pump can be a mini pump.
  • the pump can be an insulin pump
  • a patient having a disease or disorder such as heart disease or heart failure are well known to those skilled in the art (see, for example, Cecil Textbook of Medicine, 20th ed., Bennett and Plum, eds., W.B. Saunders Company, Philadelphia (1996); Harrison's Principles of Internal Medicine, 14th ed., Fauci et al., eds., McGraw-Hill, San Francisco (1998).
  • a physician can readily determine a patient having a disease or disorder suitable for treatment with the methods of the invention providing sustained release of neuregulin.
  • a patient's heart failure can be classified according to the severity of their symptoms.
  • the most commonly used classification system is the New York Heart Association (NYHA) Functional Classification. It places patients in one of four categories based on how much they are limited during physical activity, as follows: Class I: patients with cardiac disease but resulting in no limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain; Class II: patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or anginal pain; Class III: patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest.
  • Class IV patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort increases.
  • all of the NYHA classified patients (Class I-Class IV) are suitable for the methods of the invention.
  • the NYHA classified Class II and/or Class III patients are suitable for the methods of the invention.
  • neuregulin in a therapeutic cycle is administered on day 1 of the cycle and the cycle concludes with one or more days of no neuregulin administration. In some embodiments, neuregulin is administered daily for 3, 5, 7, 10 or 15 days followed by a resting period in a therapeutic cycle.
  • the study consisted of five periods, a Screening and Baseline period (Study Days ⁇ 21 to Day ⁇ 3), a treatment period (Study Days 1 through 10, with a daily infusion start time of 8 am ⁇ 2 hours), discharge (Day 11), a follow-up period (Study Days 30, 90 and 180 ⁇ 5 days) and a final follow-up visit through Day 365 ( ⁇ 5 days) to last in duration of approximately 12 months. All subjects were instructed to adhere to their current stable cardiac regimen during study participation.
  • Subjects were considered for enrollment if they had chronic heart failure with a NYHA classification of II or III, and were on a stable regimen of ACEI/angiotensin receptor blocker (ARB), beta-blocker, and/or diuretic for at least 3 months prior to receiving study medication and were anticipated to remain on the stable regimen through the treatment period. Subjects were required to have an ICD implanted at least 3 months prior to receiving study medication and have left ventricular ejection fraction (LVEF) of ⁇ 40% as determined at screening by 2-D echocardiography.
  • ARB angiotensin receptor blocker
  • LVEF left ventricular ejection fraction
  • subjects received a subcutaneous infusion of one of the following treatments: placebo (Lot number: TC2952, 250 ⁇ g per vial), or NeucardinTM (Lot number: TC2965, 250 ⁇ g/5000 EU per vial) doses of 1.2 ⁇ m/kg/day (24 EU/kg/day) or 2.0 ⁇ m/kg/day (40 EU/kg/day).
  • SC infusion pump Medtronic Paradigm 722 insulin pump. Using the Medtronic pump reservoir extract 1.6 mL of dissolved drug into the reservoir and the flow rate of the pump is 0.2 ml/h for 8 hours.
  • AEs adverse events
  • ADRs adverse reactions
  • SAEs serious adverse events
  • vital signs physical exam
  • pulse oximetry e.g parameters (e.g. QTc, QRS, HR, PR, RR, T-wave flattening/inversion, ST-elevation), anti-NeucardinTM antibody levels, pericardial fluid as measured by cardiac CT (mL, mild
  • the QTc refers to QT interval, which is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle.
  • the QT interval represents electrical depolarization and repolarization of the ventricles.
  • a lengthened QT interval is a marker for the potential of ventricular tachyarrhythmias like torsades de pointes and a risk factor for sudden death.
  • the Q, R, and S waves occur in rapid succession, do not all appear in all leads, and reflect a single event, and thus are usually considered together.
  • a Q wave is any downward deflection after the P wave.
  • An R wave follows as an upward deflection
  • the S wave is any downward deflection after the R wave.
  • the T wave follows the S wave, and in some cases an additional U wave follows the T wave.
  • Heart Rate (HR) is the speed of the heartbeat, specifically the number of heartbeats per unit of time.
  • the PR interval is also commonly termed the PQ interval, when a Q wave is measured by ECG.
  • the RR is the interval between successive Rs during ECG.
  • the RR interval variations present during resting conditions represent beat-by-beat variations in cardiac autonomic inputs.
  • CT refers to X-ray computed tomography.
  • ICD refers to implantable cardioverter defibrillator.
  • the value of LVEF % was decreased in placebo group while the value was increased in both neuregulin groups (See FIG. 1 and Table 1).
  • the mean absolute change was ⁇ 0.82%, 2.53% and 3.20% respectively in placebo group, 1.2 ⁇ g/kg and 2.0 ⁇ g/kg group (See FIG. 2 and Table 1), indicating NeucardinTM improved cardiac function by the route of subcutaneous infusion.
  • the value of LVEDV was increased in placebo group, while in 2.0 ⁇ g/kg group, the increase of LVEDV was not as much as that of placebo group, and the value was significantly decreased in 1.2 ⁇ g/kg group (See FIG. 3 and Table 2).
  • the mean absolute change was 10.22 ml, ⁇ 8.16 ml and 2.36 ml, respectively, in placebo group, 1.2 ⁇ g/kg and 2.0 ⁇ g/kg group (See FIG. 4 and Table 2).
  • Regarding the value of LVEDV 1.2 ⁇ g/kg group was better than 2.0 ⁇ g/kg group.
  • LVESV The value of LVESV was increased in placebo while the value was decreased in both neuregulin groups (See FIG. 5 and Table 3).
  • the mean absolute change was 9.33 ml, ⁇ 10.58 ml and ⁇ 5.19 ml respectively in placebo group, 1.2 ⁇ g/kg and 2.0 ⁇ g/kg group (See in FIG. 6 and table 3).
  • Regarding the value of LVESV 1.2 ⁇ g/kg group was better than 2.0 ⁇ g/kg group.
  • Both LVEDV and LVESV data showed that NeucardinTM efficiently reversed ventricular remodeling in CHF patients by the route of subcutaneous infusion.
  • Increased walk distances in 1.2 ⁇ g/kg group (41.4 m at day 30, 52.2 m at day 90, 47.7 m at day 180, 62.2 m at day 365) were all longest in the 3 groups and the increased walk distances in placebo group (19.2 m at day 30, 21.6 m at day 90, 30.5 m at day 180, 39.4 m at day 365) was longer than that in 2.0 ⁇ g/kg group (1.7 m at day 30, ⁇ 2.0 m at day 90, 11.7 m at day 180, ⁇ 24.4 m at day 365) (See FIG. 7 and Table 4).
  • the score of quality of life was increased by 4.825, 15.152 and 9.649 respectively in placebo group, 1.2 ⁇ g/kg and 2.0 ⁇ g/kg group (see also Table 5). Higher score means better quality of life.
  • the score of quality of life in the 1.2 ⁇ g/kg group was highest of the 3 groups. Scores of all 3 groups were increased while the 1.2 ⁇ g/kg group increased much more than the placebo group (See FIG. 10 ). The observed increase in quality of life score observed in the 1.2 ⁇ g/kg/day group exceeded what would have been predicted based on prior studies that utilized intravenous administration of neuregulin.
  • NT-proBNP is widely used as a diagnostic or prognostic marker for heart failure because it's typically higher in patients with worse outcome. As seen in Table 6, the level of NT-proBNP in 1.2 ⁇ g/kg group was lowest in the 3 groups and 1.2 ⁇ g/kg group was decreased much more than the placebo group.

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